title: The late endosomal adaptor molecule p14 (LAMTOR2) represents a novel regulator of Langerhans cell homeostasis.
abstract: Langerhans cells (LCs) are dendritic cells (DCs) residing in epithelia, where they critically regulate immunity and tolerance. The p14 adaptor molecule is part of the late endosomal/LAMTOR (lysosomal adaptor and mitogen-activated protein kinase and mammalian target of rapamycin [mTOR] activator/regulator) complex, thereby contributing to the signal transduction of the extracellular signaling-regulated kinase (ERK) and the mTOR cascade. Furthermore, p14 represents an important regulator for endosomal sorting processes within the cell. Mutated, dysfunctional p14 leads to a human immunodeficiency disorder with endosomal/lysosomal defects in immune cells. Because p14 participates in the regulation of endosomal trafficking, growth factor signaling, and cell proliferation, we investigated the role of p14 in mouse DCs/LCs using a conditional knockout mouse model. p14-deficient animals displayed a virtually complete loss of LCs in the epidermis early after birth due to impaired proliferation and increased apoptosis of LCs. Repopulation analysis after application of contact sensitizer leads to the recruitment of a transient LC population, predominantly consisting of short-term LCs. The underlying molecular mechanism involves the p14-mediated disruption of the LAMTOR complex which results in the malfunction of both ERK and mTOR signal pathways. Hence, we conclude that p14 acts as a novel and essential regulator of LC homeostasis in vivo.
authors.affiliation: Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria;
authors.forename: Florian
authors.initials: F
authors.lastname: Sparber
authors.forename: Julia M
authors.initials: JM
authors.lastname: Scheffler
authors.forename: Nicole
authors.initials: N
authors.lastname: Amberg
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Tripp
authors.forename: Valeska
authors.initials: V
authors.lastname: Heib
authors.forename: Martin
authors.initials: M
authors.lastname: Hermann
authors.forename: Sonja P
authors.initials: SP
authors.lastname: Zahner
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Huber
authors.forename: Patrizia
authors.initials: P
authors.lastname: Stoitzner
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Romani
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D011992:Endosomes / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006706:Homeostasis; D007801:Langerhans Cells / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D046912:Multiprotein Complexes / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D039521:CD11c Antigen; C426009:LAMTOR2 protein, mouse; D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases